We are studying the events that occur due to the inability to degrade lipid substrated in the sphingolipidoses. We are using both mouse and human model systems. In the mouse system, we are using cultured neurons from a model model of Sandhoff disease and analyzing the changes in gene expression by RNA-seq. Functional assessment of the genes that are altered in the disease neurons will be accomplished by an in vivo pooled genetic screening approach. In the human system, iPS cells from a Sandhoff disease patient were edited with CRISPR/CAS9 to enable the correction of the HEXB gene. Using the Sandhoff disease and corrected iPS cells, cerebral organoids were produced. The organoids are being studied to identify changes caused by the genetic defect in Sandhoff disease that may lead to alterations in brain development.